Editing AUA: Upper Tract Urothelial Carcinoma (2023) (section)

== Diagnosis and Evaluation ==

=== Urologyschool.com Summary ===

* '''<span style="color:#ff0000">History and Physical Exam (1):</span>'''
*#'''<span style="color:#ff0000">Personal and family history</span>'''
*#*'''<span style="color:#ff0000">To identify known hereditary risk factors for familial diseases associated with Lynch Syndrome</span>'''
* '''<span style="color:#ff0000">Laboratory (2):</span>'''
*# '''<span style="color:#ff0000">Selective ipsilateral upper tract urine cytology</span>'''
*# '''<span style="color:#ff0000">Estimated GFR/Serum Cr</span>'''
* '''<span style="color:#ff0000">Imaging (1):</span>'''
** '''<span style="color:#ff0000">CT urogram</span>'''
**Metastatic staging [not discussed in guidelines]
* '''<span style="color:#ff0000">Other (3):</span>'''
*# '''<span style="color:#ff0000">Cystoscopy to assess lower urinary tract</span>'''
*# '''<span style="color:#ff0000">Upper tract endoscopy and biopsy</span>'''
*#'''<span style="color:#ff0000">Universal histologic testing of UTUC with additional studies, such as immunohistochemical or microsatellite instability</span>'''

=== History and Physical exam ===

* <span style="color:#ff0000">'''History'''</span>
**<span style="color:#ff0000">'''Personal and family history to identify known hereditary risk factors for familial diseases associated with Lynch Syndrome'''</span>
*** '''If positive, referral for genetic counseling should be offered.'''
****Patients with Lynch Syndrome undergo routine screening due to increased life-long risk for developing associated malignancies, often occurring before 50 years of age
*** '''<span style="color:#ff0000">Lynch syndrome</span>'''
****Familial, autosomal-dominant multi-organ cancer syndrome
****'''Due to an inherited germline mutation in a group of DNA damage response genes responsible mismatch repair (MMR),''' specifically MLH1, MSH2, MSH6, PMS2, or EPCAM
*****Alterations affecting the normal function of these genes results in an accumulation of DNA errors and increases the potential for cancer development
**** '''Accounts ≈7-20% of UTUC cases in the U.S'''
*****Lynch syndrome may increase the possibility of contralateral upper tract involvement, which is an important potential clinical consideration when developing a treatment plan.
****'''<span style="color:#ff0000">Associated cancers (11):</span>'''
****#'''<span style="color:#ff0000">Colorectal (20-80%)</span>'''
****#'''<span style="color:#ff0000">Urothelial (1-18%)</span>'''
****#'''<span style="color:#ff0000">Gastric cancers (1-13%)</span>'''
****#'''<span style="color:#ff0000">Endometrial (15-60%) in females</span>'''
****#'''<span style="color:#ff0000">Ovarian cancer (1-38%) in females</span>'''
****#'''<span style="color:#ff0000">Biliary</span>'''
****#'''<span style="color:#ff0000">Small bowel</span>'''
****#'''<span style="color:#ff0000">Pancreatic</span>'''
****#'''<span style="color:#ff0000">Prostate</span>'''
****#'''<span style="color:#ff0000">Skin</span>'''
****#*Sebaceous adenoma, sebaceous epithelioma, sebaceous adenocarcinoma, keratoacanthoma, and squamous cell carcinoma[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3423888/]
****#'''<span style="color:#ff0000">Brain</span>'''

=== Laboratory ===

* '''<span style="color:#ff0000">Selective ipsilateral upper tract urine cytology</span>'''
** '''Provides supplemental histologic data to tumor biopsies'''
***'''High-grade cytology in the setting of low-grade biopsy findings indicates the likely presence of higher-risk features (e.g., high-grade tumor) missed on biopsy sampling.'''
**'''<span style="color:#ff0000">Specimen collection considerations</span>'''
***'''<span style="color:#ff0000">Can be obtained either as barbotage (saline irrigation and aspiration) or by saline irrigation with passive collection (washings)</span>'''
****'''Preferred over a voided urinary specimen''', due to (3) 
****#Improve cellular yield
****#Avoid potential contamination in case of concomitant bladder and/or prostatic urethral disease
****#Avoid theoretical dilution of the specimen from a normal contralateral unit
***'''<span style="color:#ff0000">Should be collected prior to any contrast use to avoid artifactual cellular changes from contrast solutions</span>'''
***'''<span style="color:#ff0000">Collecting selective cytology after tumor biopsy can improve the yield of cells for cytologic analysis.</span>'''
**Urine cytology is reported according to 7 categories (Paris System):
**#Non-diagnostic
**#Negative for high-grade urothelial carcinoma
**#Atypical urothelial cells
**#Suspicious for high-grade urothelial carcinoma
**#High-grade urothelial carcinoma
**#Low-grade urothelial neoplasm
**#Other malignancies
*'''<span style="color:#ff0000">Assessment of renal function</span>'''
**Can help with patient counseling, strategizing treatment sequence (operative approach and administration of systemic therapy), and determination of downstream risks of CKD and potential dialysis.
**'''Recommended test: serum creatinine (to calculate an eGFR)''' 
***For more refined evaluation, split function testing such as with differential renal scan or CT volumetric studies may be considered.
***The two formulas for monitoring eGFR commonly reported in the contemporary literature at this time are the [https://www.mdcalc.com/calc/76/mdrd-gfr-equation Modification of Diet in Renal Disease] and [https://www.mdcalc.com/calc/3939/ckd-epi-equations-glomerular-filtration-rate-gfr CKD – Epidemiology Collaboration (CKD-EPI)] equations.
**'''UTUC with associated hydronephrosis'''
***Implications on assessment of renal function
****Caused by tumor obstruction may falsely under-estimate preoperative renal function and alter decision-making around the use of neoadjuvant chemotherapy (NAC).
****Atrophy of the contralateral (unaffected) renal unit may lead to over-estimates of postoperative renal function in the setting of NU since the kidney with lower differential function will remain in situ
*** '''Renal decompression either by indwelling ureteric stent or a percutaneous nephrostomy tube placed in an uninvolved renal calyx along with oral fluid hydration for 7-14 days before re-checking eGFR will help to establish a more accurate estimation of baseline renal function.'''
****'''Ureteric stenting is the preferred method of drainage'''
*****Percutaneous nephrostomy tubes in the setting of UTUC increases risk of tract seeding and has worse quality of life

=== Imaging ===

* '''<span style="color:#ff0000">Cross-sectional imaging of the upper tract with contrast including delayed images</span>'''
** '''<span style="color:#ff0000">Preferred modality: multiphase computed tomography (CT) scan with excretory phase imaging of the urothelium</span>'''
*** Pooled sensitivity of 92%
*** Pooled specificity of 95%
** '''<span style="color:#ff0000">If contraindications to contrast-enhanced CT such as chronic kidney disease (CKD) (e.g. eGFR <30[https://medicine.yale.edu/diagnosticradiology/patientcare/policies/nephropathy/]) or untreatable allergy to iodinated contrast medium, use magnetic resonance (MR) urography</span>'''
*** MRI is less sensitive than CT, similar specificity
** '''If contraindications to multiphasic CT and MR urography, use retrograde pyelography in conjunction with non-contrast axial imaging (renal ultrasound) to assess the upper urinary tracts.'''
*PET scans
**Should not be obtained routinely 
**May be selectively considered for patients who are at risk for metastatic recurrence and are not able to have contrast enhanced CT and MRI
*Patients with findings suggestive of metastatic UTUC should be evaluated to define the extent of disease and referred to medical oncology for further management

=== Other ===
*'''<span style="color:#ff0000">Cystoscopy to assess lower urinary tract</span>'''
** Essential component of the evaluation for patients with suspected UTUC due to the risk of concurrent lower tract urothelial cancer in this population

* '''<span style="color:#ff0000">Upper tract endoscopy +/- biopsy of any identified lesion</span>''' 
**'''<span style="color:#ff0000">Diagnostic ureteroscopy</span>'''
***'''Indications for ureteroscopy or percutaneous endoscopy of the upper urinary tract (and when diagnostic and prognostic details are needed)'''
***#'''Lateralizing hematuria'''
***#'''Suspicious selective cytology'''
***#'''Radiographic presence of a mass or urothelial thickening'''
***'''<span style="color:#ff0000">Document key descriptive features of UTUC that may guide further diagnostic testing and inform therapeutic interventions as well as provide points of comparison for subsequent ureteroscopic surveillance including:'''
***# '''<span style="color:#ff0000">Location (ureteral segment, renal pelvis, calyceal sites and lower tract)'''
***#'''<span style="color:#ff0000">Size'''
***# '''<span style="color:#ff0000">Number'''
***# '''<span style="color:#ff0000">Focality'''
***# '''<span style="color:#ff0000">Appearance (sessile, papillary, flat/villous)'''
***# '''<span style="color:#ff0000">Quality of visualization </span>'''
***#*Can impact the accuracy of endoscopic inspection (e.g., bleeding, difficulty in access, tumor location, artifacts from instrumentation) and should be documented in endoscopic reports.
*** See checklist in [https://www.auanet.org/guidelines-and-quality/guidelines/non-metastatic-upper-tract-urothelial-carcinoma Guidelines Statement 2,Table 3: Standardized Upper Tract Endoscopy Suggested Reporting Elements]
** '''<span style="color:#ff0000">Biopsy of any identified lesion</span>'''
***'''Approaches (2):'''
***# '''Ureteroscopic biopsy with forceps'''
***# '''Fluoroscopically guided retrograde brush biopsy'''
*** '''Mucosal abnormalities may be difficult to biopsy effectively''' 
****'''Attempted tissue confirmation may be facilitated with the use of brush biopsies or percutaneous image-guided biopsy.'''
** '''Rare situations where endoscopic upper tract evaluation may not be necessary (2)'''
**#'''Findings would not influence decision-making, such as patients with severe co-morbidities who are ineligible for intervention or request expectant management.'''
**#'''Other diagnostic means clearly confirm the diagnosis of UTUC and thus histologic tissue confirmation is not clinically required.''' 
**#* Example would include high-grade (HG) selective cytology or other source of tissue diagnosis, and clear and convincing radiographic findings of upper tract urothelial-based tumor(s) such as an obvious enhancing, urothelial based soft-tissue filling defect on contrast-enhanced imaging with urography. 
**#**Such situations may be particularly relevant in patients with a history of HG urothelial cancer.
**'''If concomitant lower tract tumors (bladder/urethra) are discovered at the time of ureteroscopy, the lower tract tumors should be managed in the same setting as ureteroscopy.'''
*** Consensus on prioritization of procedure sequencing (managing bladder before or after same-setting ureteroscopy) is lacking and heavily scenario-dependent.
****Rationale for managing the bladder first:
*****Optimizing visualization within the bladder 
*****Avoiding back-pressure or back-washing into the upper tract in the case of post-ureteroscopy stenting 
*****Permitting final confirmation of bladder hemostasis. 
****Addressing the upper tract first may be preferred in cases of 
*****Bulky bladder tumor involvement where complete resection is not possible  
*****Bulky upper tract disease in which risk assessment is the priority. 
***Some advocate use of ureteral access sheaths to reduce risk of seeding of tumors from bladder to upper tract or from upper tract to the lower tract
****The benefits of this approach require further prospective study.
** '''In cases of existing ureteral strictures or difficult access to the upper tract, minimize risk of ureteral injury by using gentle dilation techniques such as temporary stenting (pre-stenting) and limit use of aggressive dilation access techniques such as ureteral access sheaths.'''
***Perforation or disruption of the urothelium in patients with UTUC can risk tumor seeding outside the urinary tract.
****Recognized perforation or injury events should be documented with immediate cessation of the procedure as soon as safely possible with additional steps to limit sequelae (e.g., stenting, bladder decompression with urethral catheter drainage to limit reflux, nephrostomy tube placement in cases of a completely obstructive ureteral tumor and evidence of contrast extravasation).
***Precautionary measures in cases of difficult ureteral access such as avoiding dilation or placing a stent without performing ureteroscopy and then returning one-two weeks later to repeat the procedure (pre-stenting) can decrease the risk of iatrogenic injury and provide opportunity for a safer and more successful procedure. 
**'''In cases where ureteroscopy cannot be safely performed or is not possible, an attempt at selective upper tract washing or barbotage for cytology may be made and pyeloureterography performed in cases where good quality imaging such as CT or MR urography cannot be obtained.'''
***When endoscopic examination of the involved upper tract is not possible, findings from selective cytology and retrograde pyelography may provide useful, objective and sufficient information for risk stratification . 
****Example scenarios may include washings taken at the time of percutaneous nephrostomy tube placement or during attempted retrograde ureteroscopy that is abandoned for safety concerns.
**'''At the time of ureteroscopy for suspected UTUC, ureteroscopic inspection of a radiographically and clinically normal contralateral upper tract should not be performed.'''
***Endoscopic procedures have risks for patient injury and the potential for tumor seeding in the presence of urothelial cancer. Performing upper tract endoscopy in the setting of a completely normal contralateral upper urinary tract without clinical indication or as a “screening” procedure is unnecessary, placing patients at undue risk and should not be performed
*<span style="color:#ff0000">'''Universal histologic testing of UTUC with additional studies, such as immunohistochemical (IHC) or microsatellite instability (MSI)'''</span>
**'''Routine tissue testing provides a more sensitive, first-line means to identify Lynch syndrome-associated features in tumor samples''' 
***Immunohistochemical testing 
****Can preliminarily identify the altered proteins associated with Lynch syndrome, and thus help to identify patients who may have the syndrome, who then require confirmation with further genetic (germline) testing
****Widely available
***Microsatellite instability
****Identifying the presence of Lynch syndrome-associated and MSI-high cancers also has clinical implications related to therapeutic treatment options, including identified sensitivity of urothelial cancers with mutations in DNA damage repair genes to systemic agents such as immune checkpoint inhibitors and cisplatinum-based chemotherapy

=== Optional ===
* '''Urine fluorescence in situ hybridization (FISH)'''
** May be considered adjunctively to adjudicate atypical or suspicious cytology results.
*Retrograde pyelograms
**Provide a roadmap for evaluation and possibly planning kidney-preserving strategies 
**Should be considered at initial evaluation with images retained in the patient record